Accuracy of a novel stress echocardiography pattern for myocardial bridging in patients with angina and no obstructive coronary artery disease – A retrospective and prospective cohort study

Journal Pre-proof Accuracy of a novel stress echocardiography pattern for myocardial bridging in patients with angina and no obstructive coronary artery disease – A retrospective and prospective cohort study

Vedant S. Pargaonkar, Ian S. Rogers, Jessica Su, Signe Helene Forsdahl, Ryo Kameda, Donald Schreiber, Frandics P. Chan, Hans-Christoph Becker, Dominik Fleischmann, Jennifer A. Tremmel, Ingela Schnittger PII:

S0167-5273(19)33342-X

DOI:

https://doi.org/10.1016/j.ijcard.2020.02.006

Reference:

IJCA 28336

To appear in:

International Journal of Cardiology

Received date:

3 July 2019

Revised date:

30 December 2019

Accepted date:

3 February 2020

Please cite this article as: V.S. Pargaonkar, I.S. Rogers, J. Su, et al., Accuracy of a novel stress echocardiography pattern for myocardial bridging in patients with angina and no obstructive coronary artery disease – A retrospective and prospective cohort study, International Journal of Cardiology(2020), https://doi.org/10.1016/j.ijcard.2020.02.006

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© 2020 Published by Elsevier.

Journal Pre-proof Accuracy of a Novel Stress Echocardiography Pattern for Myocardial Bridging in Patients with Angina and No Obstructive Coronary Artery Disease – A Retrospective and Prospective Cohort Study Authors: Vedant S Pargaonkar MD1, Ian S Rogers MD MPH1, Jessica Su MD1,2, Signe Helene Forsdahl MD PhD3,4, Ryo Kameda MD1, Donald Schreiber MD5, Frandics P Chan MD PhD3, Hans-Christoph Becker MD3, Dominik Fleischmann MD3, Jennifer A Tremmel MD MS1, Ingela

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Schnittger MD1

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1. Division of Cardiovascular Medicine, Stanford School of Medicine, Stanford CA, USA

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2. Department of Medicine, Yale School of Medicine, New Haven CT, USA

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3. Department of Radiology, Stanford School of Medicine, Stanford CA, USA 4. Department of Radiology, University Hospital of North Norway, Tromsø, Norway

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5. Department of Emergency Medicine, Stanford School of Medicine, Stanford CA, USA

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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation

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Brief title: Accuracy of stress echo in myocardial bridge with angina

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Funding support: None

Financial disclosure: VSP: Research fellowship support; Gilead Sciences. JAT: Honoraria; Abbott Vascular, Boston Scientific, Medtronic, Terumo; Stocks/equity; Recor. Others nothing to disclose. Address for correspondence: Ingela Schnittger, MD 300 Pasteur Dr, Room H2157, MC 5233, Stanford, CA 94305.

Journal Pre-proof Tel: (650) 723-5196 Fax: (650) 724-4034

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E-mail: [email protected]

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Journal Pre-proof Abstract Background: Myocardial bridge (MB) may cause angina in patients with no obstructive coronary artery disease (CAD). We previously reported a novel stress echocardiography (SE) pattern of focal septal buckling with apical sparing in the end-systolic to early-diastolic phase that is associated with the presence of an MB. We evaluated the diagnostic accuracy of this pattern, and prospectively validated our results.

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Methods: The retrospective cohort included 158 patients with angina who underwent both SE

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and coronary CT angiography (CCTA). The validation cohort included 37 patients who

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underwent CCTA in the emergency department for angina, and prospectively underwent SE.

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CCTA was used as a reference standard for the presence/absence of an MB, and also confirmed no obstructive CAD.

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Results: In the retrospective cohort, an MB was present in 107 (67.7%). The sensitivity,

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specificity, positive predictive value (PPV) and negative predictive value (NPV) were 91.6%, 70.6 %, 86.7% and 80%, respectively. On logistic regression, focal septal buckling and Duke

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treadmill score were associated with an MB. In the validation cohort, an MB was present in 31

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(84%). The sensitivity, specificity PPV and NPV were 90.3%, 83.3%, 96.5% and 62.5%, respectively. On logistic regression, focal septal buckling was associated with an MB. Conclusion: Presence of focal septal buckling with apical sparing on SE is an accurate predictor of an MB in patients with angina and no obstructive CAD. This pattern can reliably be used to screen patients who may benefit from advanced non-invasive/invasive testing for an MB as a cause of their angina. Key words: stress echocardiography, angina, myocardial bridge, coronary CT angiography

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Journal Pre-proof Abbreviations CAD = coronary artery disease CCTA = coronary computed tomography angiography dFFR = diastolic fractional flow reserve DTS = Duke treadmill score ECG = electrocardiogram

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ED = emergency department

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HR = heart rate

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IVUS = intravascular ultrasound

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LAD = left anterior descending artery

NPV = negative predictive value

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SE = stress echocardiography

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PPV = positive predictive value

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MB = myocardial bridge

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Journal Pre-proof 1. Introduction Patients with angina and no obstructive coronary artery disease (CAD) are common within clinical practice,[1] but remain a challenge with regard to diagnosis and treatment. Several occult coronary abnormalities can be identified in the patients, including endothelial dysfunction, microvascular dysfunction and/or a myocardial bridge (MB), which may explain their symptoms.[2,3] Although these patients have been shown to have a favorable outcome,

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their quality of life is significantly affected by repeated hospitalization, recurrent symptoms and

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repeat invasive procedures.[4] Previous studies have reported higher prevalence of MBs in

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patients with angina and no obstructive CAD compared with the general population,[2,5,6]

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raising the suspicion that MBs are a relatively common cause of angina in these patients. An MB is an anatomical variant in which the coronary artery, most frequently the left

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anterior descending artery (LAD), which normally runs through the epicardial fat, is covered by

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myocardium for a varying degree of length, depth, and location. Identifying an MB among patients with angina is challenging. Intravascular ultrasound (IVUS) is considered the current

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gold standard for detecting an MB, having a much greater accuracy than coronary

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angiography.[7,8] Coronary computed tomography angiography (CCTA) has been shown to be valuable for detecting an MB, detailing its anatomy, such as length, depth, and location, with an accuracy similar to that of IVUS.[5,9] We previously reported a novel septal motion abnormality of focal septal buckling with apical sparing during the end-systolic to early-diastolic phase during stress echocardiography (SE) that was associated with the presence of a LAD MB by IVUS and a hemodynamically significant diastolic fractional flow reserve (dFFR).[10] In this study, we assessed the diagnostic

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Journal Pre-proof accuracy of this pattern on SE to identify the presence of an LAD MB by CCTA in patients with angina with no obstructive CAD, and validated our results in a prospectively enrolled cohort. 2. Methods 2.1 Retrospective patient population We searched the Stanford Healthcare database to identify patients who underwent CCTA for any indication between December 2009 and June 2015. We found 901 patients with available

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CCTA images. Of these patients, 344 had SE images available. We removed 77 patients due to

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ineligible images, resulting in 267 patients with CCTA and SE images available. After

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exclusions (Figure 1A), the final retrospective cohort was comprised of 158 patients with no

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obstructive CAD who also underwent SE. The stress tests were completed before or after the CCTA, and were ordered at the discretion of the treating physician as an evaluation for

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typical/atypical angina,[11] shortness of breath, or dyspnea on exertion. The SE were performed

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using exercise/dobutamine according to standard laboratory protocols. 2.2 Prospective patient population

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We screened 150 patients who presented to Stanford Healthcare emergency department

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(ED) for acute chest pain who had ruled out for ST-elevation myocardial infarction (STEMI) or non-STEMI between December 2014 and January 2017. The inclusion criteria were symptom of chest pain, no diagnosis of STEMI/non-STEMI, available CCTA images, coronary stenosis<50% on CCTA, able to provide informed consent, and able to perform exercise test. A pager system informed the research team of a patient presenting to the ED with chest pain who had ruled out for a STEMI/non-STEMI. These patients were scheduled to undergo CCTA to evaluate their acute chest pain and for suspicion of acute coronary syndrome as a part of a new ED protocol. Once obstructive CAD (stenosis>50%) was ruled out by CCTA, these patients were approached

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Journal Pre-proof to prospectively undergo a SE on a separate visit. Of the total, 106 met the inclusion criteria, and 37 provided the informed consent and were included in the final analysis (Figure 1B). The study was approved by the Stanford Institutional Review Board. A written, informed consent was obtained from prospectively enrolled patients. 2.3 Stress echocardiography SE was performed according to the American Society of Echocardiography

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recommendations.[12] A standard Bruce protocol was used for exercise testing.[13] Patients

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exercised until their heart rate (HR) reached at least 85% of maximum predicted for age or

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exercise was stopped for exercise-limiting symptoms. For dobutamine SE, dobutamine was

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administered starting at a dose of 10µg/kg/min, and increased up to 50µg/kg/min, with up to 1mg of atropine given, as needed.[12]

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A 12-lead electrocardiogram (ECG) was obtained at each exercise stage. The PR-segment

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was considered the isoelectric line and ST-segment amplitude was measured at 60 milliseconds from the J point. A positive ECG was defined as the appearance of horizontal/downsloping ST-

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segment depressions of ≥1 millimeter (mm) in at least two contiguous leads for three consecutive

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beats at maximum HR.[14] The Duke treadmill score (DTS) was calculated as exercise time×(5×ST-segment deviation) - (4×exercise angina), with 0=no angina, 1=non-limiting angina, and 2=exercise-limiting angina.[15] DTSs were categorized as low-risk (score ≥+5), moderaterisk (score -10 to +4), and high-risk (score ≤-11). SE was done using an iE33 Ultrasound system (Philips Healthcare, Andover, MA). An average of 5-10 beats per loop was recorded at rest and post stress. Images were obtained in the parasternal long and short axis, apical 2-, 4-, and 3-chamber views, and analyzed on an offline

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Journal Pre-proof Xcelera workstation at normal speed, slow motion, and frame-by-frame by two blinded experienced cardiologists (I.S. and I.S.R.). We defined the presence of an MB by SE as the presence of focal septal buckling with apical sparing during the end-systolic to early-diastolic phase at stress (Supplemental figure 1A and 1B).[10] 2.4 Coronary computed tomography angiography

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All CCTAs were acquired by retrospective ECG-gated spiral scan mode, using single-

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and dual-source CT systems: Siemens Somatom Definition or Definition Flash (Siemens,

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Forchheim, Germany); GE Lightspeed VCT or GE Discovery HD750 (General Electric,

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Milwaukee, WI); and Philips Brilliance 40 (Philips, Eindhoven, The Netherlands). Patients were administered 0.4mg sublingual nitroglycerin and intravenous and/or oral metoprolol with a goal

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HR<60 beats/min before image acquisition. Reconstructed CCTA images with a slice thickness

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between 0.6 and 1.0 mm were re-evaluated on an external workstation (SyngoVia, VA30A, Siemens, Malvern, PA) by 2 blinded experienced radiologists (S.H.F. and H.C.B.). Diastolic

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datasets were reviewed. Multi- and curved-planar reformations were used for the assessment of

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the MB in 2 planes, 1 parallel and 1 perpendicular to the vessel’s course. CCTA served as reference standard for the presence/absence of an MB. The MB location was determined by measuring the distance from the LAD ostium to the bridge’s entrance. The MB length was measured in mm along the vessel axis from the disappearance of the epicardial fat plane proximally to its re-emergence distally. As defined previously by Kim et al,[9] we graded MB coverage as - the LAD running through the epicardial fat without myocardium contact (0=no MB); the LAD within the interventricular groove and in myocardium contact (1=partial coverage); full encasement of the LAD, but without visibly overlying myocardium

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Journal Pre-proof (2=unroofed); and full encasement of the LAD with visibly overlying myocardium (3=full coverage) (Supplemental figure 2). 2.5 Follow-up of the prospective validation cohort We confirmed the most recent clinical status of the patients in the prospective validation cohort using chart review and the Care Everywhere Network (Epic Systems, Verona, WI), enabling access to patient data from other participating institutions.[16] We reviewed clinical

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patient’s most recent clinical status and any hospitalization.

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visits, testing, problem lists, procedure reports, and discharge summaries to ascertain the

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2.6 Invasive anatomical and hemodynamic testing of MB

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As part of an ongoing research study, we prospectively recruited patients (n=36) who had focal septal buckling with apical sparing during SE and were confirmed to have a LAD MB by

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CCTA to undergo invasive testing. These patients had severe persistent (>3 months) angina with

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no obstructive CAD despite maximally tolerated medical therapy. These patients underwent IVUS and dFFR with Doppler flow velocity testing during dobutamine stress to study the

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anatomical and hemodynamic characteristics of their MB, as previously described.[17] We

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performed invasive angiography utilizing IVUS (Atlantis SR Pro2, Boston Scientific, Natick, MA) to measure the arterial compression (end-diastolic vessel area - end-systolic vessel area/end-diastolic vessel area)%, the MB thickness (the maximal thickness of the echolucent halo), the MB length (measured from the first proximal appearance of the halo to its distal end). We tested the hemodynamic significance of the MB by performing dFFR (diastolic coronary artery pressure divided by diastolic aortic pressure) and Doppler flow velocity by Combowire (Volcano, San Diego, CA) in the LAD. Both measurements were obtained proximal to, within, and distal to the MB at rest and during stress, using incremental intravenous infusions of up to

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Journal Pre-proof 50µg/kg/min of dobutamine, and up to 1mg intravenous atropine as needed, to reach target HR (85% of maximum predicted for age).[10,18] A dFFR≤0.76 was considered to be hemodynamically significant.[19] 2.7 Statistical analysis We verified normality of the data using the Kolmogorov–Smirnov test and histogram plots. Results are expressed as median (interquartile range). We used Chi-square tests for

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differences between categorical variables, and Student’s t-tests/Mann-Whitney rank-sum for

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continuous variables. We tested clinical characteristics and SE variables for their ability to

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identify the presence of an MB by CCTA in univariable logistic regression analyses. Variables

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with a p-value<0.2 were included in the multivariable forward stepwise logistic regression analysis. P-value<0.05 was considered statistically significant. Statistical analyses were

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performed using SPSS 22 (IBM, Armonk, NY) and NCSS 11 (NCSS, Kaysville, UT).

3.1 Retrospective cohort

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3. Results

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Table 1 shows the clinical characteristics of the patients in the retrospective cohort. Of

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the total, 88 (55.7%) were women with median age of 52 (41–61) years, while 70 (44.3%) were men with median age of 50 (43–65) years. Of the 158 patients in the retrospective cohort, 141 (89.2%) underwent exercise, while 17 (10.8%) underwent dobutamine SE. The median duration between SE and CCTA was 46 (2– 108) days. An MB was present in 113 (71.5%) by SE and 107 (67.7%) by CCTA. The median MB length was 10 (4–21)mm, with a coverage of 1 (1–3), located at a distance of 40 (26–60)mm from the LAD ostium. On comparing stress-testing parameters, patients with an MB by CCTA

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Journal Pre-proof had a significantly higher baseline, maximum exercise, and recovery HR. They also had a lower DTS, and a higher prevalence of a moderate- to high-risk DTS (Supplemental table 1). No traditional segmental wall motion abnormalities were detected at rest/stress. The inter-observer agreement for focal septal buckling with apical sparing on SE was excellent [kappa statistic - 0.87 (95% CI 0.79 – 0.95, p<0.001)]. The sensitivity of focal septal buckling with apical sparing on SE to identify the presence of an MB was 91.6% (95% CI 89.8–93.4%),

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the specificity was 70.6% (95% CI 66.3–74.9%). The positive predictive value (PPV) and

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negative predictive value (NPV) were 86.7% (95% CI 84.6–88.9%) and 80% (95% CI 75.9 –

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84.0%), respectively (Figure 2A).

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Supplemental table 2 shows the univariable logistic regression analysis to identify variables associated with the presence of an MB by CCTA. On multivariable regression analysis,

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focal septal buckling with apical sparing on SE and DTS were associated with the presence of an

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MB by CCTA (Supplemental table 3). 3.2 Prospective validation cohort

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Table 2 shows the clinical characteristics of the patients in the prospective validation

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cohort. Of the total, 20 (54%) were women with the age of 53 (42-60) years, and 17 (45.9%) were men with the age of 50 (46-58) years. All patients presented with severe acute left-sided chest pain. At presentation, none of the patients had ST-segment elevation ≥1 mm, elevated cardiac biomarkers, or another likely explanation of their chest pain, like pulmonary embolism, pulmonary hypertension, pericarditis, hypertrophic cardiomyopathy, valvular heart disease or obstructive CAD by CCTA.

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Journal Pre-proof Patients in the retrospective cohort had a higher prevalence of hyperlipidemia and a lower prevalence of a family history of CAD than those in the prospective validation cohort (Supplemental table 4). The median duration between SE and CCTA was 31 (5–62) days. An MB was present in 28 (75.7%) by SE and 31 (83.8%) by CCTA. Supplemental table 5 represents the stress test parameters in patients with and without an MB by CCTA. Patients with an MB by CCTA had

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greater ST-segment depression at peak HR than patients with no MB.

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The sensitivity of focal septal buckling with apical sparing on SE to identify the presence

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of an MB in the validation cohort was 90.3%, while the specificity was 83.3%. The PPV and

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NPV were 96.5% and 62.5%, respectively (Figure 2B).

Supplemental table 6 shows the univariable logistic regression analysis to identify

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variables associated with the presence of an MB by CCTA. On multivariable regression analysis,

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only focal septal buckling with apical sparing on SE was associated with the presence of an MB by CCTA (OR 4.61; 95% CI 2.18–8.33; p=0.01).

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3.3 Follow-up of the prospective validation cohort

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Over the follow-up of 1.99 (0.62–2.84) years, there were no major adverse cardiovascular events including death, myocardial infarction, stroke, or revascularization. In patients with an MB by CCTA, 14 (45.1%) had recurrent angina and 4 (12.9%) had re-hospitalization for a cardiovascular reason. One patient had an abnormal dFFR on invasive hemodynamic testing of their MB. This patient underwent surgical unroofing of their MB because of intolerable anginal symptoms despite maximally tolerated medical therapy. 3.4 Invasive anatomical and hemodynamic testing of MB

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Journal Pre-proof In patients (n=36) who underwent prospective invasive testing, IVUS confirmed the presence of an MB in all patients. Supplemental table 7 represents the anatomical and hemodynamic characteristics of the MB. All patients had a dFFR≤0.76 within or distal to the MB. By CCTA, these patients had a significantly longer MB [23 (16.9 – 37)mm vs. 10 (4–21)mm, p<0.001] and greater coverage [2 (1–3) vs. 1 (1–2), p<0.001] than the rest. 4. Discussion

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In this study, we report the diagnostic accuracy of a novel SE pattern of focal septal

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buckling with apical sparing during SE in identifying the presence of an MB by CCTA in

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patients with angina and no obstructive CAD. We found that this pattern identified the presence

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of an MB in a retrospective cohort with a sensitivity and specificity of 91.6% and 70.6%, respectively. We validated these findings in a prospective patient cohort, showing that focal

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septal buckling with apical sparing identified an MB with a sensitivity and specificity of 90%

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and 83%, respectively. The accuracy of this echo pattern in identifying an MB is similar to the accuracy with which we can detect obstructive atherosclerotic CAD by identifying a new wall

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motion abnormality.[20,21] Our findings strongly suggest that this distinct SE pattern in patients

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with angina and no obstructive CAD can help identify an MB as a potential cause of their angina. It is important to emphasize that to fully identify the “bridge pattern” on SE, the acquired images should include at least five, complete, consecutive cardiac cycles, which ensures that translation artifacts in the images during heavy respiration do not mask the finding. Furthermore, a frame-by-frame analysis should be employed in cases of uncertain septal motion, also the ability of playing the images in slow motion, forward and backward. We have found that the focal septal buckling is most apparent in the mid-antero-septal wall in the parasternal long-axis

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Journal Pre-proof and apical 3-chamber views. It is also appreciated in the mid-septum in the apical 4-chamber view. The apical sparing is best seen in the latter. Historically, MBs were thought to be universally benign, because the coronary artery fills during diastole, while compression from the bridge occurs during systole. However, studies using IVUS and Doppler demonstrated that arterial compression can persist into early diastole, thus affecting flow.[22] Our group previously proposed a model of ischemia caused by the

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Venturi effect within an MB.[10] The lumen diameter inside the MB decreases during end-

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systole to early diastole, resembling a narrowed section of a pipe. When blood passes through

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this narrowed segment of the vessel, velocity increases to satisfy the principle of conservation of

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energy by the continuity equation. At the same time, the pressure must decrease to satisfy the Bernoulli Principal, thus decreasing the filling pressure to the septal branches within the tunneled

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section of the artery. This pressure drop within an MB may explain the focal septal buckling with

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apical sparing visualized during SE. When the diameter of the LAD distal to the MB returns toward normal, there will be pressure recovery. This may result in less or no impact on the

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perfusion pressure in the distal vessel and its branches, thus resulting in no discernable wall

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motion abnormality in the apical area. Identifying MBs as a potential cause of angina can be challenging. MBs are not associated with traditional wall motion abnormalities on SE in patients with angina and no obstructive CAD, as also demonstrated in the current study.[23] In addition, MBs are wellknown to be overlooked on invasive coronary angiography, with only ~5% showing the classic milking effect previously described.[24,25] Instead, IVUS can detect an MB with greater sensitivity and specificity, and is considered the invasive gold standard for detection of an MB.[8] Still, even when an MB is identified, its hemodynamic significance is unknown, with the

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Journal Pre-proof majority of MBs likely being only an incidental finding. It has been shown that mean adenosine fractional flow reserve (FFR), an important invasive clinical decision-making tool used in the evaluation of a fixed coronary artery stenosis, is generally not useful in assessing the hemodynamic significance of an MB.[19,22] Instead, dFFR with dobutamine stress is the preferred test.[19] In this study, we show that a characteristic septal motion during SE can identify the

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presence of an MB with a high sensitivity and specificity in patients with angina and no

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obstructive CAD, although this may not indicate whether the MB is hemodynamically

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significant. We previously showed that patients with a hemodynamically significant MB have a

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reduced change in septal strain on SE.[26] This degree of reduction was associated with hemodynamic significance by invasive dFFR. Hence, an accurate identification of an MB by the

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characteristic septal motion, along with an assessment of the change in strain on SE, may help

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stratify patients with an MB according to hemodynamic significance. In the current study, we also showed that patients who were invasively studied all had a hemodynamically significant

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dFFR. These patients had a significantly longer MB and greater coverage on CCTA, which was

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shown to be associated with hemodynamic significance.[5] Further studies are needed to determine the accuracy of focal septal buckling with apical sparing on SE in identifying the hemodynamic significance of an MB. In our study, 12 patients from both the cohorts combined had false negative diagnosis of an MB by SE. Of these, three patients had a superficial and short MB, while in other three, MB was present very distal in the LAD, and two patients had submaximal stress test. These factors may have limited the magnitude of septal buckling resulting in false negative finding.

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Journal Pre-proof In our retrospective cohort, 67.7% of patients had at least one MB by CCTA. The prevalence of an MB reported in the literature varies greatly, ranging from 25% using invasive imaging to 85% in autopsy studies.[27,28] Studies utilizing CCTA have reported a prevalence of ~30% in the general population.[6] Based on our previous work, the prevalence seen in patients with angina in the absence of obstructive CAD is nearly double,[2,5] raising the suspicion of MBs as a relatively common cause of angina in this patient subset.

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Another important finding of our study was the high prevalence of an MB (84%) in

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patients presenting to the ED with acute chest pain and were later ruled out for a myocardial

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infarction with no obstructive CAD by CCTA. This high prevalence highlights the relevance of

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investigating for the presence of a potentially hemodynamic significant MB as a cause of chest pain in this patient population. Importantly, we found that 45.4% of patients with an MB had

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recurrent anginal symptoms, while 13% had at least one re-hospitalization for acute chest pain

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within two years. This suggests that patients with recurrent chest pain and no obstructive CAD, who have a SE or CCTA suggestive of an MB may benefit from advanced

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4.1 Limitations

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imaging/hemodynamic testing to identify the potential cause of their symptoms.

This is a relatively small, single-center study; however, ours is the first study to report and prospectively validate the diagnostic accuracy of focal septal buckling with apical sparing in diagnosing the presence of an MB. In addition, the identification of an MB tells nothing of its hemodynamic significance. While we invasively evaluated patients and demonstrated an abnormal dFFR in all of them, these patients had persistent anginal symptoms despite maximally tolerated medical therapy that were severe enough to warrant an invasive testing, hence cannot be used to demonstrate that focal septal buckling on SE represents hemodynamic significance.

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Journal Pre-proof The dobutamine stress dFFR that we used to study the hemodynamic significance of an MB, was first reported in a small single cohort study [19] and its validation in a larger study is warranted. Also, angina in the absence of obstructive CAD may be caused by other occult coronary abnormalities including endothelial and microvascular dysfunction. As a part of the prospective study protocol, patients were required to return to the hospital at a later date to undergo a SE, which limited the enrollment response. Likewise, longer-term outcome data were not available

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predicting cardiovascular outcomes in patients with an MB.

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for this study, so we cannot determine how the presence of this septal motion is useful in

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5. Conclusion

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The novel finding of focal septal buckling with apical sparing during the end-systolic to early-diastolic phase on SE is an accurate predictor of an MB in patients with angina and no

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obstructive CAD. This echo pattern can reliably be used for screening patients who may benefit

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from advanced non-invasive/invasive testing for an MB as a cause of their angina.

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Journal Pre-proof References [1]

M.R. Patel, E.D. Peterson, D. Dai, J.M. Brennan, R.F. Redberg, H. V Anderson, R.G. Brindis, P.S. Douglas, Low diagnostic yield of elective coronary angiography, N Engl J Med. 362 (2010) 886–895. doi:10.1056/NEJMoa0907272\r362/10/886 [pii].

[2]

B.K. Lee, H.S. Lim, W.F. Fearon, A.S. Yong, R. Yamada, S. Tanaka, D.P. Lee, A.C. Yeung, J.A. Tremmel, Invasive Evaluation of Patients with Angina in the Absence of

B.D. Johnson, L.J. Shaw, S.D. Buchthal, C.N. Bairey Merz, H.W. Kim, K.N. Scott, M.

-p

[3]

ro

doi:10.1161/CIRCULATIONAHA.114.012636.

of

Obstructive Coronary Artery Disease, Circulation. 131 (2015) 1054–1060.

re

Doyle, M.B. Olson, C.J. Pepine, J. den Hollander, B. Sharaf, W.J. Rogers, S. Mankad, J.R. Forder, S.F. Kelsey, G.M. Pohost, Prognosis in women with myocardial ischemia in the

lP

absence of obstructive coronary diseaseresults from the National Institutes of Health-

na

National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE)., Circulation. 109 (2004) 2993–2999.

F. Radico, M. Zimarino, F. Fulgenzi, F. Ricci, M. Di Nicola, L. Jespersen, S.M. Chang,

Jo

[4]

ur

doi:10.1161/01.CIR.0000130642.79868.B2.

K.H. Humphries, M. Marzilli, R. De Caterina, Determinants of long-term clinical outcomes in patients with angina but without obstructive coronary artery disease: a systematic review and meta-analysis., Eur. Heart J. 39 (2018) 2135–2146. doi:10.1093/eurheartj/ehy185. [5]

S.H. Forsdahl, I.S. Rogers, I. Schnittger, S. Tanaka, T. Kimura, V.S. Pargaonkar, F.P. Chan, D. Fleischmann, J.A. Tremmel, H.-C. Becker, Myocardial bridges on coronary computed tomography angiography ― Correlation with intravascular ultrasound and

17

Journal Pre-proof fractional flow reserve, Circ. J. 81 (2017) 1894–1900. doi:10.1253/circj.CJ-17-0284. [6]

L. La Grutta, G. Runza, G. Lo Re, M. Galia, V. Alaimo, E. Grassedonio, T. V Bartolotta, R. Malago, C. Tedeschi, F. Cademartiri, M. De Maria, A.E. Cardinale, R. Lagalla, M. Midiri, Prevalence of myocardial bridging and correlation with coronary atherosclerosis studied with 64-slice CT coronary angiography., Radiol. Med. 114 (2009) 1024–1036. doi:10.1007/s11547-009-0446-y. J. Ge, R. Erbel, H.J. Rupprecht, L. Koch, P. Kearney, G. Görge, M. Haude, J. Meyer,

of

[7]

ro

Comparison of intravascular ultrasound and angiography in the assessment of myocardial

K. Tsujita, A. Maehara, G.S. Mintz, H. Doi, T. Kubo, C. Castellanos, J. Liu, J. Yang, C.

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[8]

-p

bridging., Circulation. 89 (1994) 1725–1732. doi:10.1161/01.CIR.89.4.1725.

Oviedo, T. Franklin-Bond, N. Dasgupta, S. Biro, L. Dani, G.D. Dangas, R. Mehran, A.J.

lP

Kirtane, A.J. Lansky, E.M. Kreps, M.B. Collins, G.W. Stone, J.W. Moses, M.B. Leon,

na

Comparison of Angiographic and Intravascular Ultrasonic Detection of Myocardial Bridging of the Left Anterior Descending Coronary Artery, Am. J. Cardiol. 102 (2008)

P.J. Kim, G. Hur, S.Y. Kim, J. Namgung, S.W. Hong, Y.H. Kim, W.R. Lee, Frequency of

Jo

[9]

ur

1608–1613. doi:10.1016/j.amjcard.2008.07.054.

myocardial bridges and dynamic compression of epicardial coronary arteries: a comparison between computed tomography and invasive coronary angiography., Circulation. 119 (2009) 1408–1416. doi:10.1161/CIRCULATIONAHA.108.788901. [10] S. Lin, J.A. Tremmel, R. Yamada, I.S. Rogers, C.M. Yong, R. Turcott, M. V. McConnell, R. Dash, I. Schnittger, A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation., J. Am. Heart Assoc. 2 (2013) e000097. doi:10.1161/JAHA.113.000097.

18

Journal Pre-proof [11] G.A. Diamond, A clinically relevant classification of chest discomfort., J. Am. Coll. Cardiol. 1 (1983) 574–575. [12] P.A. Pellikka, S.F. Nagueh, A.A. Elhendy, C.A. Kuehl, S.G. Sawada, American Society of Echocardiography recommendations for performance, interpretation, and application of stress echocardiography. - PubMed - NCBI, J. Am. Soc. Echocardiogr. 20 (2007) 1021– 1041. doi:http://dx.doi.org/10.1016/j.echo.2007.07.003.

of

[13] R.A. Bruce, F.W. Lovejoy, Normal respiratory and circulatory pathways of adaptation in

ro

exercise., J. Clin. Invest. 28 (1949) 1423–1430. doi:10.1172/JCI102207.

-p

[14] S.D. Fihn, J.M. Gardin, J. Abrams, K. Berra, J.C. Blankenship, A.P. Dallas, P.S. Douglas,

re

J.M. Foody, T.C. Gerber, A.L. Hinderliter, S.B. King, P.D. Kligfield, H.M. Krumholz, R.Y.K. Kwong, M.J. Lim, J.A. Linderbaum, M.J. MacK, M.A. Munger, R.L. Prager, J.F.

lP

Sabik, L.J. Shaw, J.D. Sikkema, C.R. Smith, S.C. Smith, J.A. Spertus, S. V. Williams,

na

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, J. Am. Coll. Cardiol. 60

ur

(2012) e44–e164. doi:10.1016/j.jacc.2012.07.013.

Jo

[15] L.J. Shaw, E.D. Peterson, L.K. Shaw, K.L. Kesler, E.R. DeLong, F.E. Harrell Jr., L.H. Muhlbaier, D.B. Mark, Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups, Circulation. 98 (1998) 1622–1630. doi:10.1161/01.CIR.98.16.1622. [16] Epic Systems Corporation, Care Everywhere Network, (n.d.). https://www.epic.com/careeverywhere/. [17] J.H. Boyd, V.S. Pargaonkar, D.H. Scoville, I.S. Rogers, T. Kimura, S. Tanaka, R. Yamada, M.P. Fischbein, J.A. Tremmel, R.S. Mitchell, I. Schnittger, Surgical Unroofing

19

Journal Pre-proof of Hemodynamically Significant Left Anterior Descending Myocardial Bridges, Ann. Thorac. Surg. 103 (2017) 1443–1450. doi:http://dx.doi.org/10.1016/j.athoracsur.2016.08.035. [18] M. Kersemans, F. Van Heuverswyn, M. De Pauw, P. Gheeraert, Y. Taeymans, B. Drieghe, Hemodynamic effect of myocardial bridging., Circ. Cardiovasc. Interv. 2 (2009) 361–362. doi:10.1161/CIRCINTERVENTIONS.109.855395.

of

[19] J. Escaned, J. Cortes, A. Flores, J. Goicolea, F. Alfonso, R. Hernandez, A. Fernandez-

ro

Ortiz, M. Sabate, C. Banuelos, C. Macaya, Importance of diastolic fractional flow reserve

-p

and dobutamine challenge in physiologic assessment of myocardial bridging., J. Am. Coll.

re

Cardiol. 42 (2003) 226–233.

[20] B.D. Beleslin, M. Ostojic, A. Djordjevic-Dikic, R. Babic, M. Nedeljkovic, G. Stankovic,

lP

S. Stojkovic, J. Marinkovic, I. Nedeljkovic, J. Stepanovic, J. Saponjski, Z. Petrasinovic, S.

na

Nedeljkovic, V. Kanjuh, Integrated evaluation of relation between coronary lesion features and stress echocardiography results: the importance of coronary lesion

ur

morphology, J. Am. Coll. Cardiol. 33 (1999) 717–726. doi:https://doi.org/10.1016/S0735-

Jo

1097(98)00613-5.

[21] T.H. Marwick, Stress echocardiography, Heart. 89 (2003) 113–118. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767520/. [22] J. Ge, A. Jeremias, A. Rupp, M. Abels, D. Baumgart, F. Liu, M. Haude, G. Görge, C. Von Birgelen, S. Sack, R. Erbel, New signs characteristic of myocardial bridging demonstrated by intracoronary ultrasound and Doppler, Eur. Heart J. 20 (1999) 1707–1716. doi:10.1053/euhj.1999.1661. [23] V.S. Pargaonkar, Y. Kobayashi, T. Kimura, I. Schnittger, E.K.H. Chow, V.F. Froelicher,

20

Journal Pre-proof I.S. Rogers, D.P. Lee, W.F. Fearon, A.C. Yeung, M.L. Stefanick, J.A. Tremmel, Accuracy of non-invasive stress testing in women and men with angina in the absence of obstructive coronary artery disease, Int. J. Cardiol. 282 (2019) 7–15. doi:10.1016/j.ijcard.2018.10.073. [24] J. Noble, M.G. Bourassa, R. Petitclerc, I. Dyrda, Myocardial bridging and milking effect of the left anterior descending coronary artery: Normal variant or obstruction?, Am. J. Cardiol. 37 (1976) 993–999. doi:10.1016/0002-9149(76)90414-8.

of

[25] O. Soran, G. Pamir, C. Erol, C. Kocakavak, I. Sabah, The incidence and significance of

ro

myocardial bridge in a prospectively defined population of patients undergoing coronary

-p

angiography for chest pain., Tokai J. Exp. Clin. Med. 25 (2000) 57–60.

re

[26] Y. Kobayashi, J.A. Tremmel, Y. Kobayashi, M. Amsallem, S. Tanaka, R. Yamada, I.S. Rogers, F. Haddad, I. Schnittger, Exercise Strain Echocardiography in Patients With a

lP

Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study., J.

na

Am. Heart Assoc. 4 (2015) e002496. doi:10.1161/JAHA.115.002496. [27] S. Mohlenkamp, W. Hort, J. Ge, R. Erbel, Update on myocardial bridging., Circulation.

ur

106 (2002) 2616–2622.

Jo

[28] M.T. Corban, O.Y. Hung, P. Eshtehardi, E. Rasoul-Arzrumly, M. McDaniel, G. Mekonnen, L.H. Timmins, J. Lutz, R.A. Guyton, H. Samady, Myocardial bridging: Contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies, J. Am. Coll. Cardiol. 63 (2014) 2346–2355. doi:10.1016/j.jacc.2014.01.049.

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Journal Pre-proof Figure legends Figure 1A. Flow chart describing retrospective cohort selection Figure 1B. Flow chart describing prospective cohort selection Figure 2A. (1) Accuracy of focal septal buckling with apical sparing on stress echo to identify the presence of an MB in the retrospective cohort; (2) 2X2 table representing MB by stress echo and by CCTA

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Figure 2B. (1) Accuracy of focal septal buckling with apical sparing on stress echo to

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identify the presence of an MB by CCTA in the prospective validation cohort; (2) 2X2 table

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representing MB by stress echo and by CCTA

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VSP: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing - Original Draft, Writing - Review & Editing, Visualization, ISR: Conceptualization,

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Methodology, Investigation, Resources, Writing - Review & Editing; JS: Conceptualization,

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Methodology, Validation, Investigation, Writing - Review & Editing; SHF: Methodology, Investigation, Writing - Review & Editing; RK: Methodology, Investigation, Writing - Review

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& Editing; DS: Conceptualization, Resources, Writing - Review & Editing, Supervision; FPC:

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Resources, Writing - Review & Editing, Supervision; HCB: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing; DF: Investigation, Resources, Writing Review & Editing, Supervision; JAT: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Supervision, Funding acquisition; IS: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Supervision, Funding acquisition, Project administration

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Journal Pre-proof Table 1. Clinical characteristics of patients in the retrospective cohort Characteristic

Age, yrs Male sex, n (%)

MB by CCTA

No MB

n=107

n=51

50 (38–60)

55 (44–65)

0.051

37 (34.6)

33 (64.7)

<0.001

Race/Ethnicity, n (%)

p-value

0.07 1 (0.9)

0

18 (16.8)

Hispanic/Latino

11 (10.3) 5 (4.7)

Native Hawaiian/Pacific Islander

2 (1.9)

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Black/African American

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Asian

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American Indian/Alaskan native

Caucasian

16 (31.4) 1 (1.9) 3 (5.9) 2 (3.9)

55 (51.4)

24 (47.1)

14 (13.1)

5 (9.8)

25.7 (23.5–29.1)

25.7 (23.5–28.5)

0.96

25 (23.4)

13 (25.5)

0.77

17 (15.9)

15 (29.4)

0.047

34 (31.8)

23 (45.1)

0.10

Hyperlipidemia, n (%)

53 (49.5)

29 (56.9)

0.38

Family history of CAD, n (%)

14 (11.8)

6 (13.1)

0.81

Beta-blocker usage, n (%)

34 (31.8)

17 (33.3)

0.84

Anti-hypertensive medication, n (%)

36 (33.6)

16 (31.4)

0.77

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Other

Current/past smoking, n (%)

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Hypertension, n (%)

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Diabetes mellitus, n (%)

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Body mass index, kg/m2

CAD = coronary artery disease, CCTA = coronary computed tomography angiography, MB = myocardial bridge

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Journal Pre-proof Table 2. Clinical characteristics of patients in the prospective validation cohort Characteristic

Age, yrs Male sex, n (%)

MB by CCTA

No MB

n=31

n=6

52 (46–60)

49 (46–68)

0.82

12 (38.7)

5 (83.3)

0.04

Race/Ethnicity, n (%)

p-value

0.44

5 (16.1)

Hispanic/Latino

3 (9.7)

Black/African American

2 (6.4)

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Asian

0 2 (33.3)

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1 (3.2)

Caucasian

0 0

15 (48.4)

2 (33.3)

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American Indian/Alaskan native

7 (22.6)

2 (33.3)

27.8 (22.7–30.8)

29.5 (26.1–34.3)

0.48

6 (19.3)

2 (33.3)

0.77

5 (16.1)

2 (33.3)

0.32

10 (2.3)

2 (50)

0.40

9 (29.0)

2 (33.3)

0.83

Family hx of CAD, n (%)

11 (35.5)

3 (50)

0.50

Beta-blocker usage, n (%)

5 (16.1)

2 (33.3)

0.34

Other

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Body mass index, kg/m2

Hypertension, n (%)

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Hyperlipidemia, n (%)

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Diabetes mellitus, n (%)

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Current/past smoking, n (%)

CAD = coronary artery disease, CCTA = coronary computed tomography angiography, MB = myocardial bridge

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Journal Pre-proof Highlights Focal septal buckling with apical sparing on stress echo accurately predicts an MB



This pattern can help identify an MB as a potential cause of angina



And can be useful to screen patients who may benefit from further testing for an MB

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Figure 1

Figure 2

Figure 3

Figure 4